Upon injury, the skin epidermis must undergo immediate repair mechanism to restore its barrier function to prevent dehydration and invasion of harmful pathogens. Wound repair of the skin epidermis involves activation, migration, proliferation, and differentiation of keratinocytes. In particular, the re-epithelialization of the wounded area requires skin epithelial stem cells, which migrate in both from the surrounding epidermis and also from the hair follicle. However, very little is known about the signals that activate stem cell migration and the molecular mechanisms directing their migration during wound repair. How do hair follicle stem cells respond to wound signals? What are the signaling pathways that direct stem cell migration during wound repair? Which population(s) of epithelial stem cells is responsible for repairing the epidermis and generation of new hair follicles? In this research plan, I propose to: (1) Identify the cells within the hair follicle that contribute to wound repair; (2) Purify and characterize the cells within the hair follicle that contribute to wound repair; (3) Monitor and characterize cells as they migrate during wound repair; and (4) Perform functional studies on molecules that may be involved in cell migration and re-epithelialization during wound repair. I plan to exploit mouse models that allow lineage tracing of skin stem cells and their progeny during the process of wound healing. This enables characterization and isolation of skin stem cells that contribute to wound repair and generation of new hair follicles. A genome-wide gene profiling will be conducted to examine the changes in gene expression, and to identify molecules and signal pathways that may be involved in migration of the skin stem cells. I will perform further functional assays to validate the participation of the candidate molecules in the migration process. Findings from this research plan will contribute to our understanding of the molecular mechanism of skin stem cell migration upon injury and provide answers to many fundamental questions in the stem cell field. PUBLIC HEALTH RELEVANCE: The main focus of this research proposal is to understand the molecular mechanisms involved in the activation and migration of epithelial stem cells during wound repair and to study the population(s) of stem cells in the hair follicles that may contribute to epidermis regeneration and new hair follicle formation at the wound sites. Since the molecular interactions between tumor and its microenvironment are similar to a wounding situation in many aspects, it is plausible to hypothesize that many of the same signals mobilizing skin stem cells to leave their original niche upon wounding may as well mobilize cancer stem cells and cause tumor metastasis. Thus, this proposed research is likely to provide insights on mechanisms of cancer progression, and the knowledge acquired from this research plan will advance our current understanding of how tissues heal wounds, as well as have implications for regenerative medicine.